Recent evidence indicates that two newly identified subsets of T lymphocytes, regulatory T (Treg) cells and IL-17-producing T helper (Th17), are playing reciprocal roles in immune responses. Treg cells act as suppressors of the immune response against tumors and infectious pathogens (Wilczynski et al. Front Biosci. 2008 Jan. 1; 13:2275-89.; Rouse & Suvas. J. Immunol. 2004 Aug. 15; 173(4):2211-5.; herein incorporated by reference in their entireties). Among various molecular mechanisms involved in Treg expansion, is the tolerogenic enzyme indoleamine 2,3 dioxygenase (IDO). This key enzyme has been shown to be involved in both tumor- and pathogen associated tolerance (Munn & Mellor. J Clin Invest. 2007 May; 117(5):1147-54.; Popov & Schultze. J Mol Med. 2008 February; 86(2):145-60).; herein incorporated by reference in their entireties). The role of Th17 cells in cancer has been less well characterized, however cytokine, IL-17, has been shown to increase recruitment of macrophages to tumor sites and stimulate generation of cytotoxic T cells, indicating that Th17 cells play an anti-tumor role (Kolls & Lindén. Immunity. 2004 October; 21(4):467-76.; herein incorporated by reference in its entirety). The evidence for the involvement of Th17 cells in anti-infection immune responses is abundant. There are strong indications that Th17 cells, their key cytokine, IL-17, as well as the Th17-expanding cytokine, IL-23, all play important roles in protection against pathogens (Jin et al. Autoimmunity. 2008 March; 41(2):154-62.; herein incorporated by reference in its entirety).
Attempts have been made in the past to inhibit Treg cells to improve immune response. Because Treg cells express high affinity IL-2 receptors (CD25), experiments using anti-CD25 antibodies, or IL-2 conjugated with toxins have been carried out in various experimental tumor models and in human trials with mixed results (Schabowsky et al. Curr Opin Investig Drugs. 2007 December; 8(12):1002-8.; herein incorporated by reference in its entirety). Similarly, depleting Treg cells by anti-CD25 antibodies failed to improve protective immunity against BCG in mice (Quinn et al. Eur J. Immunol. 2008 March; 38(3):695-705.; herein incorporated by reference in its entirety). Other immune stimulating approaches, using antibodies against CTLA-4 or GITR have been unsuccessful (Schabowsky et al. Curr Opin Investig Drugs. 2007 December; 8(12):1002-8.; herein incorporated by reference in its entirety). Thus, taken together, current strategies to inhibit Treg suffer from significant pitfalls.
Immunotherapy is an appealing anti-cancer treatment strategy. However, despite the fact that tumor cells express many immunogenic antigens, the immune system often fails to recognize or respond to them. This occurs because cancer cells utilize mechanisms that render the immune system tolerant, thereby evading immune recognition and/or eradication (Zou. Nat. Rev Cancer. 2005 April; 5(4):263-74; herein incorporated by reference in its entirety). Similarly, many pathogens have evolved sophisticated strategies to manipulate and evade their host immune system (Rouse. J Immunol. 2004 Aug. 15; 173(4):2211-5; herein incorporated by reference in its entirety). Consequently, attempts to establish preventive or therapeutic immunity using conventional immunization protocols have often met with disappointing results (Orme. J Leukoc Biol. 2001 July; 70(1):1-10.; Guinn et al. Mol. Ther. 2007 June; 15(6):1065-71; herein incorporated by reference in their entireties).
There have been no meaningful attempts to investigate the therapeutic utility of Th17 stimulation against tumors. In infectious diseases, on the other hand, there has been progress. The growing realization that the IL-23/Th17 axis is critical in both primary protective response and vaccination (Khader & Cooper. Cytokine 2008 February; 41(2):79-83.; herein incorporated by reference in its entirety), has prompted IL-23 gene transfer experiments in mice (Happel et al. Infect Immun. 2005 September; 73(9):5782-8.; Wozniak et al. Infect Immun. 2006 January; 74(1):557-65.; herein incorporated by reference in their entireties). The results have indeed confirmed that the IL-23 gene product can act as an adjuvant during BCG vaccination; however, while these findings are encouraging, the feasibility of mass administration of genes or their recombinant products is questionable, given the cost involved, the possibility of triggering neutralizing antibodies or allergic responses and lingering concerns about the safety of gene delivery.